© World History Archiv/Topfoto
Oswald Avery (1877–1955), who discovered that deoxyribonucleic acid (DNA) serves as genetic material.
Oswald Avery (1877–1955), who discovered that deoxyribonucleic acid (DNA) serves as genetic material.
After Fred Griffith had discovered, in 1928, that one form of pneumococci could be ‘transformed’ into another by absorbing what seemed to be genetic material (see here), other researchers tried to find out just what it was that was being passed from one form of the bacteria to another. The key developments took place at the Rockefeller Institute in New York, in a laboratory headed by Oswald Avery, who had been working on pneumonia since 1913, and took a keen interest in Griffith’s discovery.
In 1931, the Rockefeller team found that it wasn’t even necessary to use mice in the transformation process. Just by growing R pneumococci in a Petrie dish also containing dead S pneumococci they were able to transform the live R type into the S type. This began a quest to identify the transforming agent. By using a process of alternate freezing and heating, the cells of a colony of Stype bacteria were broken apart so that their interior contents mixed with the other fragments of the cells in a liquid goo. By spinning test tubes containing this goo in a centrifuge, the solid pieces of cell-wall debris were forced to the bottom of the tubes, leaving above them a light liquid (the inner contents of the cells). Sure enough, the liquid from inside the cells was able to transform R-type cells into the S type.
All of this was established by 1935. At this point, Avery brought in a young researcher, Colin MacLeod, to work with him on an intensive investigation of the genetically active liquid from inside the cells. They were later joined by Maclyn McCarty. It took them nearly ten years to complete the project, not least because along the way they had to eliminate all the ingredients that were not causing the transformation, until they were left with the culprit. Paraphrasing the words Arthur Conan Doyle put into the mouth of his character Sherlock Holmes, once they had eliminated the impossible, what was left, however improbable it might have seemed at the start of the investigation, must be the answer.
It seemed at first that the most likely transforming agent might be protein, as proteins are very complex molecules that contain a lot of information. But when the team treated the liquid derived from the cells of Stype bacteria with an enzyme that was known to chop protein molecules into little pieces (a protease), they found that this had no effect on the ability of the liquid to carry out the transforming process. Another possibility was that the effect was associated with the polysaccharides that coated the Stype bacteria. So Avery’s team used an enzyme which broke the polysaccharides apart, but again with no effect on the transforming process. At this point, in a careful series of chemical steps, the team removed all traces of proteins and polysaccharides from their brew, and set about a painstaking chemical analysis of what was left behind. It had to be a nucleic acid (see here), revealed by the proportions of carbon, hydrogen, nitrogen, and phosphorus that it contained. Further tests revealed that it was DNA, not RNA.
The discovery was published in 1944, in the first of a series of scientific papers reporting the identification of the transforming agent as DNA. They stopped short of saying that DNA must be the material that genes are made of, although Avery did speculate about this possibility privately, including in a letter to his brother Roy, a bacteriologist. But the suggestion that DNA, not protein, carried the hereditary information stored inside cells was so shocking that the biological community at large did not immediately take it on board. They were still largely convinced that DNA was too simple a molecule to do the job, held back by the ‘tetranucleotide hypothesis’ (see here). In addition, as the active material inside the cells of bacteria is floating around loose inside the cell and not packaged into genes and chromosomes, many biologists at the time thought that it was too big a leap to jump from DNA as the transforming factor revealed by Griffith’s work, to DNA as the active component in true genetics. Nevertheless, the Avery–MacLeod–McCarty experiment attracted wide interest and stimulated more work by microbiologists and geneticists on the physical and chemical nature of genes. It is now recognized as the beginning of molecular genetics. If ever a team deserved the Nobel Prize, Avery, MacLeod, and McCarty did – but somehow, they were overlooked. It would be several years before the balance of evidence in favour of DNA as the genetic material became overwhelming, thanks to another brilliant experiment (see here).